It is widely recognized that despite the enormous progress in vaccine development, a large part of the population does not receive any coverage due to poor access and low socioeconomic conditions. Importantly for several life-threatening infectious diseases such as HIV, tuberculosis or malaria there are no available vaccines. Moreover bioweapon threats could include the deliberate release of an infectious agent that causes one or more of a variety of different diseases. Currently there are no safe and effective vaccines in the pipeline for many biological agents that may pose high risk to national security, due to increased person-to person transmissibility, disease severity and social disruption. For the aforementioned reasons current research focuses not only on the design of new vaccines against a broad range of diseases but also on the optimization of the existing ones, aiming to increased potency, safety, rapid distribution and possibly self-administration. Since many vaccines under investigation are either subunit or split pathogens or highly purified recombinant molecules, they lack the inherent immunostimulatory properties of the original pathogen. It is therefore important to consider the incorporation of adjuvants in the formulations and/or the design of novel delivery systems that will take advantage of the host's immune battery and enhance the vaccine immunogenicity. To address these issues we propose to deliver the vaccine in the skin and combine it with lead adjuvants. We will investigate the role of novel fused cytokines and immunomodulatory chemokines secreted in the skin following vaccine delivery that can alter the magnitude and the quality of immune responses to vaccines. We also plan to take advantage of our extensive experience with microneedles to design novel dissolving polymer microneedle formulations to encapsulate the adjuvanted vaccine while preserving the functional properties of the components. For the purpose of this study, we will use a licensed subunit influenza vaccine as a model antigen because it can benefit from the addition of adjuvants, because of the challenging nature of the virus that continuously mutates to evade host immune defenses and the availability of excellent animal models for immunogenicity, challenge and protection studies. We are motivated by our findings that influenza vaccine delivery to the skin with dissolving polymer or metal microneedle patches induces enhanced immunogenicity, as demonstrated by the longevity of immune responses compared to conventional systemic immunization in small animal models. Our preliminary studies in non-human primates with microneedles delivering unadjuvanted influenza vaccine have also demonstrated the potential of skin immunization. We hypothesize that the appropriate adjuvants will increase immunogenicity of the vaccine in the young and elderly population, as well as the breadth of immunity, which is a critical issue in case of unpredicted outbreaks from emerging strains. Finally, we expect that in the long term, adjuvanted influenza vaccination using a dissolving polymer microneedle patch will enable safe self-administration and more rapid distribution of the vaccine in the case of large epidemics or new pandemics.